Microglia comprise the immune system of the central nervous system; inappropriate activation of these cells and the resultant inflammation has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's (PD) disease. Inhibition of microglial activation is an obvious approach to prevent orat least delay progression of neurodegeneration. A major expected drawback to large scale, long term inhibition of the brain's immune system is increased susceptibility to cancer and infection. Among the many neurotoxic compounds produced and released by microglia is an excitotoxin which activates NMDA receptors and may be a neuron-specific toxin critical for progression of neurodegenerative diseases. If production and release of this toxin can be selective inhibited, it should be possible to target the major microglial pathway involved in neuronal killing while preserving beneficial cytotoxic pathways involved in protecting against cancer and infection. The aims of this project are 1) to characterize the microglia-derived neuron-specific toxin basal forebrain cholinergic and mesencephalic dopaminergic neuronal cultures, the cultures which preferentially die in AD and PD; 2) to characterize pathways involved in the activation and inhibition of production of the microglia-derived neuron-specific toxin. Drugs that preferentially inhibit the neuron-specific toxin producing pathway are potential therapeutic agents against neurodegenerative disease. Conversely, drugs that show promise against AD and PD will be examined in this model system to see if they inhibit the production or action of the neuron- specific toxin.